Human Transporters

LAT2New

LAT2 (L-type amino acid transporter 2)

Alias: LPI-PC1

Gene name: Solute carrier family 7 member 8 (SLC7A8)

Summary

LAT2 is a ubiquitously expressed, broad-specificity transporter for neutral amino acids, thyroid hormones, and amino acid-like xenobiotics. The mode of transport is obligatory exchange for amino acids but unidirectional uptake for thyroid hormones. As opposed to LAT1, LAT2 is positioned basolaterally in absorptive epithelia and functions in the transepithelial transport, rather than the cellular accumulation, of amino acids. LAT2 contributes to the renal reabsorption of amino acids, transplacental amino acid transport, glutamine/glutamate cycling in the brain, and the intestinal absorption of methionine. The contribution of LAT2 to drug transport across the blood-brain barrier is negligible relative to LAT1. Also, while LAT2 is overexpressed in several cancer types and has been shown to foster tumor growth, compared to LAT1 there is less evidence to support a universal role for LAT2 in cancer. As there are no known drug substrates or inhibitors of LAT2, the regulatory guidelines do not currently recommend in vitro investigation of LAT2 liabilities.

Localization

LAT2 is expressed ubiquitously in the body, with the highest levels measured in the kidney. LAT2 expression was also detected in the prostate, testes, ovaries, gastrointestinal tract, brain, liver, spleen, skeletal muscle, heart, and lung [Pineda, J Biol Chem 1999; Park, Arch Pharm Res 2005]. In polarized cells such as the renal proximal tubules and the intestinal epithelium, LAT2 tends to be restricted to the basolateral membrane domain [Rossier, J Biol Chem 1999], although in the placental syncytiotrophoblast it is distributed to both the apical (maternal) and basolateral (fetal) surfaces, showing colocalization with the apically expressed LAT1 [Widdows, FASEB J 2015]. In the mouse brain, highest Lat2 expression is observed in the microglia, followed by astrocytes and neurons [Braun, Glia 2011].

Function, physiology, and clinically significant polymorphisms

The SLC7A8 gene is located on chromosome 14q11.2. The longest of its four transcript variants encodes a ~58-kDa protein that displays 55% amino acid identity with its closest relative, LAT1 (SLC7A5). Similar to other members of the heteromeric amino acid transporter (HAT, SLC7) family, LAT2 has 12 transmembrane domains with both the N- and C-termini located intracellularly, and forms a covalent heterodimer via a disulfide bridge with an escort protein (the ‘heavy chain’) that is required for its plasma membrane localization but does not participate in transport. The heavy chain partner of LAT2, shared with LAT1 as well as all other HATs except for b0,+AT, is the 4F2hc (SLC3A2) glycoprotein [Wagner, Am J Physiol Cell Physiol 2001].

Both LAT1 and LAT2 are typically modelled as obligatory exchangers that accept a similar set of amino acids on the intracellular and extracellular sides of the membrane, albeit with much higher affinities on the extracellular side [Meier, EMBO J 2002]. The obligatory nature of the exchange mechanism was challenged by a single work that provided evidence for a unidirectional facilitated transport component [Widdows, FASEB J 2005]. As suggested by its basolateral localization at biological barriers like the gut, kidney, and placenta, the function of LAT2 is poised towards transcellular amino acid transport, whereas LAT1 is rather envisaged as a key mediator of amino acid uptake into growing cells.

LAT2 is characterized by broad substrate specificity for both small and large neutral (zwitterionic) amino acids [Pineda, J Biol Chem 1999], as opposed to LAT1 that prefers large neutral amino acid substrates. LAT2 accepts L-enantiomers of Tyr, Phe, Trp, Thr, Asn, Ile, Cys, Ser, Leu, Val, Gln, His, Ala, Met, as well as Gln (in the order of Km increasing from 35.9 to 265 μM) [Segawa, J Biol Chem 1999]. Further endogenous substrates of LAT2 include thyroid hormones, especially triiodothyronine (T3) and 3,3’-diiodothyronine [Zevenbergen, Endocrinology 2015], the neurotransmitter precursor L-DOPA [Pinto, FASEB J 2013; Barollo, PLoS One 2016], as well as nitrosothiols like S-nitrosocysteine that mediate some biological effects of nitric oxide [Li, J Biol Chem 2005]. Unlike amino acids, thyroid hormones are transported in the inward (uptake) direction only [Krause and Hinz, Mol Cell Endocrinol 2017].

Non-physiological substrates of LAT2 known so far are amino acid-like xenobiotics. LAT2 transports methylmercury, an environmental toxicant structurally reminiscent of methionine, across the placenta [Balthasar, Int J Mol Sci 2017], and it facilitates the uptake of the widely used herbicide glyphosate across epithelia [Xu, Chemosphere 2016]. It has, however, not been reported to transport any drug to a pharmacologically relevant extent. Although LAT2 is expressed in the brain microvasculature, its contribution to the transport of L-DOPA or pregabalin across the blood-brain barrier is minor or none, respectively [Kageyama, Brain Res 2000; Takahashi, Pharm Res 2018].

To date, no specific inhibitor of LAT2 has been identified. The generic system L inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is typically used in vitro to block LAT2, and the prototypical inhibitor of the glutamine transporter ASCT2, L-γ-glutamyl-p-nitroanilide (GPNA), has also been shown to interfere with system L transporters including LAT2 [Chiu, Amino Acids 2017].

Since Slc7a8-knockout mice display no other apparent defect but aminoaciduria, the single unique physiological function of LAT2 seems to be the reabsorption of small neutral amino acids from urine [Braun, Biochem J 2011]. In the basolateral membrane of proximal tubule cells, LAT2 cooperates with MCT10/TAT1, utilizing the aromatic amino acids exported by the latter as exchange equivalents [Park, Arch Pharm Res 2005; Vilches, J Am Soc Nephrol 2018]. The lack of additional phenotypes in Scl7a8-KO mice suggests that transporters with overlapping specificities can replace or complement LAT2 in other roles such as the renal reabsorption of large neutral amino acids or the cellular uptake of thyroid hormones. Although its contribution may be dispensable due to functional redundancies, LAT2 has been shown to be involved in transplacental amino acid transport [Gaccioli, Reprod Biol Endocrinol 2015], the efflux of glutamine from astrocytes as a part of the glutamate/GABA-glutamine cycle in the brain [Leke, Adv Neurobiol 2016], and the intestinal absorption of methionine under circumstances when the principal methionine transporter, LAT4, is blocked or overwhelmed [Mastrototaro, IUBMB Life 2016].

Of the almost 14.000 SLC7A8 gene variants recorded in the dbSNP database, only 2 are marked as likely pathogenic, and none is annotated in OMIM. Nevertheless, four rare coding variants with decreased transport activity (p.Val302Ile, p.Arg418His, p.Thr402Met, p.Val460Glu) were speculated to play a causative role in age-related hearing loss [Espino Guarch, Elife 2018], and three other coding variants (p.Pro16Arg, p.Gly18Trp, p.Ser29Phe) as well as one intronic SNP (c.1016‐49T > C) were associated with the increased risk of autism spectrum disorder, probably via restricting the availability of key amino acids like tryptophan in the developing brain [Cascio, Mol Genet Genomic Med 2020]. Moreover, genetic defects of LAT2, especially in combination with dysfunctional MCT10/TAT1, are implicated in cataract formation [Knöpfel, Front Physiol 2019], and some polymorphisms affect aging-related phenotypes such as muscle strength in the elderly [Crocco, Aging (Albany NY) 2018].

Clinical significance

While LAT1 is overexpressed in many cancer types and its positive effect on tumor growth through the mTOR pathway is well-established, a similarly universal role for LAT2 is not supported by available evidence [Wang and Holst, Am J Cancer Res 2015]. There are a few reports, though, suggesting a pro-oncogenic role for LAT2 in tumors. LAT2 overexpression is associated with poor prognosis in pancreatic cancer, and like LAT1 it acts by stimulating the mTOR pathway [Feng, J Exp Clin Cancer Res 2018]. Besides LAT1, LAT2 was also found to be overexpressed in neuroendocrine tumors, where the two are collectively responsible for increased uptake of L-DOPA [Barollo, PLoS One 2016]. Finally, progesterone-dependent overexpression of LAT2 was documented in uterine leiomyoma cells and could be inhibited with the progesterone antagonist mifepristone; however, the significance of LAT2 overexpression remained unclear [Luo, J Clin Endocrinol Metab 2009].

Regulatory requirements

As there are no known drug substrates or inhibitors of LAT2, the FDA and EMA guidelines do not currently recommend in vitro investigation of LAT2 liabilities.

Table: Summary information for LAT2

Location

Endogenous substrates

In vitro substrates used experimentally

Substrate drugs

Inhibitors

ubiquitous; highest expression in the renal proximal tubule (basolateral side)

neutral amino acids, thyroid hormones (T3, 3,3’-T2), L-DOPA, nitrosothiols

no preference (the choice of substrate depends on the experimental question)

none known

BCH, GPNA

 

References

Balthasar C, Stangl H, Widhalm R, Granitzer S, Hengstschläger M, Gundacker C. Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter. Int J Mol Sci. 2017;18(8):1730. Published 2017 Aug 8. Doi:10.3390/ijms18081730

Barollo S, Bertazza L, Watutantrige-Fernando S, et al. Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors. PLoS One. 2016;11(5):e0156044. Published 2016 May 25. doi:10.1371/journal.pone.0156044

Braun D, Wirth EK, Wohlgemuth F, et al. Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8. Biochem J. 2011;439(2):249–255. doi:10.1042/BJ20110759

Cascio et al. Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder. Mol Genet Genomic Med. 2020 Jan;8(1):e1036.

Chiu M, Sabino C, Taurino G, et al. GPNA inhibits the sodium-independent transport system L for neutral amino acids. Amino Acids. 2017;49(8):1365–1372. doi:10.1007/s00726-017-2436-z

Crocco P, Hoxha E, Dato S, et al. Physical decline and survival in the elderly are affected by the genetic variability of amino acid transporter genes. Aging (Albany NY). 2018;10(4):658–673. doi:10.18632/aging.101420

Espino Guarch M, Font-Llitjós M, Murillo-Cuesta S, et al. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. Elife. 2018;7:e31511. Published 2018 Jan 22. doi:10.7554/eLife.31511

Feng M, Xiong G, Cao Z, et al. LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. J Exp Clin Cancer Res. 2018;37(1):274. Published 2018 Nov 12. doi:10.1186/s13046-018-0947-4

Gaccioli F, Aye IL, Roos S, et al. Expression and functional characterisation of System L amino acid transporters in the human term placenta. Reprod Biol Endocrinol. 2015;13:57. Published 2015 Jun 9. doi:10.1186/s12958-015-0054-8

Kageyama et al. The 4F2hc/LAT1 Complex Transports L-DOPA Across the Blood-Brain Barrier. Brain Res 2000. PMID 11011012

Knöpfel EB, Vilches C, Camargo SMR, et al. Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans. Front Physiol. 2019;10:688. Published 2019 Jun 4. doi:10.3389/fphys.2019.00688

Krause G, Hinz KM. Thyroid hormone transport across L-type amino acid transporters: What can molecular modelling tell us?. Mol Cell Endocrinol. 2017;458:68–75. doi:10.1016/j.mce.2017.03.018

Leke R, Schousboe A. The Glutamine Transporters and Their Role in the Glutamate/GABA-Glutamine Cycle. Adv Neurobiol. 2016;13:223–257. doi:10.1007/978-3-319-45096-4_8

Li S, Whorton AR. Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols. J Biol Chem. 2005;280(20):20102–20110. doi:10.1074/jbc.M413164200

Luo X, Yin P, Reierstad S, et al. Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. J Clin Endocrinol Metab. 2009;94(11):4533–4539. doi:10.1210/jc.2009-1286

Mastrototaro L, Sponder G, Saremi B, Aschenbach JR. Gastrointestinal methionine shuttle: Priority handling of precious goods. IUBMB Life. 2016;68(12):924–934. doi:10.1002/iub.1571

Meier C, Ristic Z, Klauser S, Verrey F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J. 2002;21(4):580–589. doi:10.1093/emboj/21.4.580

Park SY, Kim JK, Kim IJ, et al. Reabsorption of neutral amino acids mediated by amino acid transporter LAT2 and TAT1 in the basolateral membrane of proximal tubule. Arch Pharm Res. 2005;28(4):421–432.

Pineda M, Fernández E, Torrents D, et al. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999;274(28):19738–19744. doi:10.1074/jbc.274.28.19738

Pinto V, Pinho MJ, Soares-da-Silva P. Renal amino acid transport systems and essential hypertension. FASEB J. 2013;27(8):2927–2938. doi:10.1096/fj.12-224998

Rossier G, Meier C, Bauch C, et al. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem. 1999;274(49):34948–34954. doi:10.1074/jbc.274.49.34948

Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem. 1999;274(28):19745–19751. doi:10.1074/jbc.274.28.19745

Takahashi Y, Nishimura T, Higuchi K, et al. Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line. Pharm Res. 2018;35(12):246. Published 2018 Oct 29. doi:10.1007/s11095-018-2532-0.

Vilches C, Boiadjieva-Knöpfel E, Bodoy S, et al. Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids. J Am Soc Nephrol. 2018;29(6):1624–1635. doi:10.1681/ASN.2017111205

Wagner CA, Lang F, Bröer S. Function and structure of heterodimeric amino acid transporters. Am J Physiol Cell Physiol. 2001;281(4):C1077–C1093. doi:10.1152/ajpcell.2001.281.4.C1077

Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res. 2015;5(4):1281–1294. Published 2015 Mar 15.

Widdows KL, Panitchob N, Crocker IP, et al. Integration of computational modeling with membrane transport studies reveals new insights into amino acid exchange transport mechanisms. FASEB J. 2015;29(6):2583–2594. doi:10.1096/fj.14-267773

Xu J, Li G, Wang Z, et al. The role of L-type amino acid transporters in the uptake of glyphosate across mammalian epithelial tissues. Chemosphere. 2016;145:487–494. doi:10.1016/j.chemosphere.2015.11.062

Zevenbergen C, Meima ME, Lima de Souza EC, et al. Transport of Iodothyronines by Human L-Type Amino Acid Transporters. Endocrinology. 2015;156(11):4345–4355. doi:10.1210/en.2015-1140

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